KR100521839B1 - Novel flavone derivatives, their pharmaceutically acceptable salts and their pharmaceutical compositions - Google Patents
Novel flavone derivatives, their pharmaceutically acceptable salts and their pharmaceutical compositions Download PDFInfo
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- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
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- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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Abstract
본 발명은 하기 화학식 1 내지 3으로 표시되는 신규한 플라본 유도체, 약학적으로 허용가능한 그의 염 및 이들을 유효성분으로 함유하는 약학적 조성물에 관한 것으로, 보다 상세하게는 하기 화학식 1 내지 3으로 표시되는 플라본 유도체 또는 약학적으로 허용가능한 이들의 염은 염증유도성 효소인 시클로옥시게나아제-2(cyclooxygenase-2, 이하 "COX-2"라고 약칭함) 및 유도성 나이트릭 옥사이드 신타아제(inducible nitric oxide synthase, 이하 "iNOS"이라고 약칭함)의 발현 또는 활성을 저해함으로써 염증질환치료, 면역조절 또는 암질환 예방에 유용하게 사용될 수 있다.The present invention relates to novel flavone derivatives represented by the following formulas (1) to (3), pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them as active ingredients, more particularly flavones represented by the following formulas (1) to Derivatives or pharmaceutically acceptable salts thereof include the proinflammatory enzymes cyclooxygenase-2 (abbreviated as "COX-2") and inducible nitric oxide synthase. By inhibiting the expression or activity of "iNOS" hereinafter, it can be usefully used for the treatment of inflammatory diseases, immunomodulation or cancer disease prevention.
화학식 1Formula 1
상기 식에서, 각각 R1 내지 R3은 명세서 중에 정의된 바와 같다.Wherein R 1 to R 3 are each as defined in the specification.
화학식 2Formula 2
상기 식에서, 각각 R1 내지 R3은 명세서 중에 정의된 바와 같다.Wherein R 1 to R 3 are each as defined in the specification.
화학식 3Formula 3
상기 식에서, 각각 R1 내지 R2은 명세서 중에 정의된 바와 같다.Wherein R 1 to R 2 are each as defined in the specification.
Description
본 발명은 염증유발성 효소들의 발현 또는 활성 억제제에 관한 것으로, 보다 상세하게는 신규한 플라본 유도체 또는 약학적으로 허용가능한 그의 염을 유효성분으로 함유하는 시클로옥시게나아제-2(cyclooxygenase-2, 이하 "COX-2"라고 약칭함) 및 유도성 나이트릭 옥사이드 신타아제(inducible nitric oxide synthase, 이하 "iNOS"이라고 약칭함)의 발현 또는 활성 억제제에 관한 것이다.The present invention relates to inhibitors of the expression or activity of inflammatory enzymes, and more particularly cyclooxygenase-2 (hereinafter referred to as cycloactivegenase-2) containing a novel flavone derivative or a pharmaceutically acceptable salt thereof as an active ingredient. And "inducible nitric oxide synthase" (hereinafter referred to as "iNOS").
시클로옥시게나아제(cyclooxygenase, 이하 "COX"라고 약칭함)는 아라키돈산(arachidonic acid, 이하 "AA"라고 약칭함)으로부터 프로스타글란딘(prostaglandins, 이하 "PGs"이라고 약칭함)의 생합성에 관여하는 효소로, 생체내에서 COX-1과 COX-2의 두가지 이성 효소로 존재하는 것으로 밝혀져 있다(Cell, 83, 345, 1995). COX-1은 구조성 효소(constitutive enzyme)로, 정상상태에서 발현하여 위장관보호, 신장기능조절과 같은 신체의 항상성의 유지에 관여하는 반면, COX-2는 유도성 효소(inducible enzyme)으로, 염증이나 기타 면역 반응시 세포분열인자(mitogen)나 사이토카인류(cytokines)에 의해 세포내 발현이 증가하는 것으로 알려져 있다(J. Biol. Chem., 271, 33157, 1996). 비스테로이드성 소염진통제(Nonsteroidal antiinflammatory drug, 이하 "NSAIDs"라고 약칭함)들은 COX-2 효소를 억제함으로써 소염 진통효과를 나타내지만, COX-1 효소 또한 불필요하게 억제하기 때문에 위장관 출혈이나 신장 독성과 같은 부작용이 발생하는 것으로 알려져 있다(Proc. Natl. Acad. Sci. USA, 91, 3228 (1994); Proc.Natl. Acad. Sci. USA, 91, 12013(1994)). 따라서, COX-2를 선택적으로 저해할 수 있는 물질에 관한 연구가 활발히 진행되고 있고(WO 9606840; Bioorg. Med. Chem. Lett. 5, 2377, 1995; Ann. Report. Med. Chem., 211, 1997), 최근 셀레브렉스(celebrex) 또는 바이옥스(vioxx)가 COX-2를 선택적으로 억제하면서 위장관 출혈 등의 부작용을 완화시킨 약물로 개발되어 시판되고 있다.Cyclooxygenase (abbreviated as "COX") is an enzyme involved in the biosynthesis of prostaglandins (abbreviated as "PGs") from arachidonic acid (abbreviated as "AA"). It has been shown to exist in vivo as two isoenzymes, COX-1 and COX-2 ( Cell , 83, 345, 1995). COX-1 is a constitutive enzyme, expressed in steady state and involved in the maintenance of the body's homeostasis, such as gastrointestinal protection and renal function control, while COX-2 is an inducible enzyme It is known that intracellular expression is increased by mitogens and cytokines during other immune responses ( J. Biol. Chem. , 271, 33157, 1996). Nonsteroidal antiinflammatory drugs (abbreviated as "NSAIDs") have anti-inflammatory analgesic effects by inhibiting COX-2 enzymes, but they also inhibit COX-1 enzymes unnecessarily, such as gastrointestinal bleeding or kidney toxicity. Side effects are known to occur ( Proc. Natl. Acad. Sci . USA, 91, 3228 (1994); Proc. Natl. Acad. Sci . USA, 91, 12013 (1994)). Therefore, studies on substances capable of selectively inhibiting COX-2 are actively conducted (WO 9606840; Bioorg. Med. Chem. Lett. 5, 2377, 1995; Ann. Report. Med. Chem. , 211, 1997), celebrex or vioxx have recently been developed and marketed as drugs that selectively inhibit COX-2 and alleviate side effects such as gastrointestinal bleeding.
그리고, 선종성 폴립은 대장점막에서 PGE2를 증가시키는데, 상기 PGE2는 AA 대사과정에서 COX에 의해 초래되는 것이기 때문에 COX를 억제시키는 COX-2 억제제에 의해 대장암 등의 발암과정을 억제시킬 수 있고, 따라서, COX-2 억제제는 대장암을 위시한 암의 예방요법제로도 사용할 수 있다.In addition, adenomatous polyps increase PGE 2 in the colonic mucosa, and since PGE 2 is caused by COX during AA metabolism, COX-2 inhibitors that inhibit COX can inhibit carcinogenesis such as colorectal cancer. Therefore, COX-2 inhibitors can also be used as a prophylactic agent for cancer including colon cancer.
나이트릭 옥사이드(nitric oxide, 이하 "NO"라고 약칭함)는 나이트릭 옥사이드 신타아제(nitric oxide synthase, NOS)에 의해 L-아르기닌으로부터 생성된다. NO는 처음에 아세틸콜린(acetylcholin) 및 브라드키닌(bradykinin)과 같은 물질의 작용을 매개하여 혈관을 확장시키는 인자로 알려졌고(Furchgott RF and Zawadzki JV, 1980) 그후, NO가 대식세포(macrophage)의 항종양 및 항균작용에 반응하는 것으로 밝혀져 있다(Hibba, 1987). iNOS는 건강한 조직에서는 거의 발현되지 않고, 면역적인 공격이나 상처를 받았을 때 나타나며, 염증유발 상태에서 iNOS는 신경세포, 성상세포(astrocytes) 및 내피세포를 포함하는 대부분의 조직에서 나타날 수 있고 염증의 매개물질로 작용한다(Nathan and Xie, 1994). NO의 형성은 또한, 류마티스성 관절염, 전신성 홍반성 낭창, 궤양성 대장염 등과 같은 자가면역질환과 홍반, 혈관 확장 등과 같은 전형적인 염증증상에서 증가되고, 이러한 증상은 iNOS 저해제에 의해 호전되는 것으로 알려져 있다.Nitric oxide (abbreviated as "NO") is produced from L-arginine by nitric oxide synthase (NOS). NO was initially known to be a factor that dilates blood vessels by mediating the actions of substances such as acetylcholin and bradykinin (Furchgott RF and Zawadzki JV, 1980), after which NO is a term for macrophage. It has been shown to respond to tumor and antimicrobial activity (Hibba, 1987). iNOS is rarely expressed in healthy tissues and appears when subjected to an immune attack or injury.Inflammatory conditions, iNOS can appear in most tissues, including neurons, astrocytes and endothelial cells and mediates inflammation. It acts as a substance (Nathan and Xie, 1994). The formation of NO is also increased in autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, and typical inflammatory symptoms such as erythema, vasodilation, etc., and these symptoms are known to be improved by iNOS inhibitors.
한편, 현재까지 3000여종 이상으로 알려져 있는 식물 플라본 유도체들은 항염증, 항알러지, 항암활성 등 많은 생물학적 활성이 알려져 있다(Havsteen, Biochemical Pharmacology 32, 1114, 1983). 이들 중 4종 내지 5종은 순수물질의 형태로 기관지 천식 치료제, 골다공증 치료제 등의 의약품으로 사용되고 있으나, 대부분의 경우 식물추출물에 함유되어 있는 상태로 인체에 섭취되어 사용되고 있고, 실제 하루 평균섭취량은 보고에 따르면 50 내지 1000 mg으로 알려져 있다. 그리고, 이들이 나타내는 생물활성 중 항염증 또는 항알러지 작용은 여러 연구자들에 의해 1960년대부터 동물모델에서 증명되어 왔다(Kim et al., Nat. Prod. Sci. 2, 1, 1996). 수종의 플라본 유도체들의 항염증 작용기전에 대한 연구결과도 많이 발표되어 왔으나, 1980년 수종의 플라본 유도체들이 에이코사노이드(eicosanoid) 생성효소인 COX 및 리폭시게나아제(lipoxygenase, 이하 "LOX"라고 약칭함)를 저해한다는 것이 발표된 이후(Bauman et al., Prostaglandins 20, 627, 1980), 많은 연구자들은 이들 유도체들의 아라키돈산(arachidonic acid, 이하 "AA"라고 약칭함) 대사효소에 대한 작용 및 in vivo 항염증 또는 항알러지 작용에 대한 연구를 계속 진행하여 왔다. 실제로 플라본들은 화학구조에 따라 COX 또는 LOX를 저해한다는 많은 논문이 발표되었으며(Ferrandiz et al., Pharmazie 45, 206, 1990; Laughton et al., Biochemical Pharmacology 42, 1673, 1991) 현재도 계속적으로 연구가 진행중이고, 최근 수종의 플라본 유도체들이 다른 염증유도성 효소인 iNOS의 발현을 억제한다는 것이 확인되었다(Liang et al., Carcinogenesis 20, 1945, 1999; Kim et al., Biochemical Pharmacology 58, 759, 1999; Chi et al., Biochemical Pharmacology 61, 1195, 2001). 또 다른 특정구조의 플라본 유도체들이 염증유발과 관련있는 종양괴사인자-α(tumor necrosis factor-α, 이하 "TNF-α"라고 약칭함) 또는 인터루킨-1(interleukin-1, 이하 "IL-1"이라고 약칭함) 등의 염증유발 사이토카인(cytokine)들의 생성을 억제한다는 것이 알려져 있다(Cho et al., J. Ethnopharmacology 70, 127, 2000); Krakauer et al., FEBS Letter 500, 52, 2001). 그러나, 지금까지 발견된 수종의 플라본 유도체들은 COX-2 및 iNOS의 발현 또는 활성 억제능력이 부족하므로 염증질환 치료, 면역조절 또는 암질환 예방 효과가 제한적이므로 COX-2 및 iNOS의 발현 또는 활성 억제능력이 보다 우수한 새로운 구조의 염증유발성 효소 억제제의 개발이 요구되어 왔다.On the other hand, plant flavone derivatives known to more than 3000 species so far are known for many biological activities such as anti-inflammatory, anti-allergic, anti-cancer activity (Havsteen, Biochemical Pharmacology 32, 1114, 1983). Four to five of them are in the form of pure substances and used as medicines such as bronchial asthma and osteoporosis, but in most cases, they are used in humans in the state of plant extracts, and the average daily intake is reported. According to known from 50 to 1000 mg. And their anti-inflammatory or anti-allergic activity has been demonstrated in animal models by the researchers since the 1960s (Kim et al., Nat. Prod. Sci. 2, 1, 1996). There have been many studies on the anti-inflammatory mechanisms of several flavone derivatives, but in 1980 several species of flavone derivatives were referred to as eicosanoid synthase COX and lipoxygenase (hereinafter referred to as "LOX"). Since it was announced that it was inhibited (Bauman et al., Prostaglandins 20, 627, 1980), many researchers have reported that these derivatives act against arachidonic acid (abbreviated as "AA") and metabolize enzymes in vivo. Research into inflammation or anti-allergic activity has been ongoing. Indeed, many papers have published that flavones inhibit COX or LOX depending on their chemical structure (Ferrandiz et al., Pharmazie 45, 206, 1990; Laughton et al., Biochemical Pharmacology 42, 1673, 1991). It is ongoing and several recent flavone derivatives have been shown to inhibit the expression of another proinflammatory enzyme iNOS (Liang et al., Carcinogenesis 20, 1945, 1999; Kim et al., Biochemical Pharmacology 58, 759, 1999; Chi et al., Biochemical Pharmacology 61, 1195, 2001). Other specific flavone derivatives are known as tumor necrosis factor-α ("TNF-α") or interleukin-1 ("IL-1") associated with inflammation. It is known to inhibit the production of proinflammatory cytokines, such as (Cho et al., J. Ethnopharmacology 70, 127, 2000); Krakauer et al., FEBS Letter 500, 52, 2001). However, the several flavone derivatives discovered so far lack the ability to inhibit the expression or activity of COX-2 and iNOS, thus the ability to inhibit the expression or activity of COX-2 and iNOS is limited because of their limited effect on the treatment of inflammatory diseases, immunomodulation or cancer diseases. There has been a need for the development of new, better structured proinflammatory enzyme inhibitors.
본 발명의 목적은 우수한 COX-2 또는 iNOS의 발현 또는 활성 억제활성을 갖는 신규 플라본 유도체 또는 약학적으로 허용가능한 그의 염을 제공할 뿐만 아니라 이들 유도체들의 의약학적 용도를 제공하고자 하는 것이다. It is an object of the present invention to provide novel flavone derivatives or pharmaceutically acceptable salts thereof having excellent expression or activity inhibiting activity of COX-2 or iNOS as well as to provide medicinal uses of these derivatives.
상기 목적을 달성하기 위해서, 본 발명은 하기 화학식 1 내지 3으로 표시되는 신규 플라본 유도체 또는 약학적으로 허용가능한 그의 염을 제공한다.In order to achieve the above object, the present invention provides a novel flavone derivative or a pharmaceutically acceptable salt thereof represented by the following formula (1).
화학식 1Formula 1
상기 식에서 R1, R2 및 R3는 각각 1) 메톡시기 또는 O-당이거나 2) 메틸설파닐기 또는 할로겐이다.Wherein R 1 , R 2 and R 3 are each 1) a methoxy group or an O-sugar or 2) a methylsulfanyl group or halogen.
화학식 2Formula 2
상기 식에서, R1은 히드록시기, 메톡시기 또는 메틸설파닐기(m은 1 내지 3)이고, R2는 할로겐(n은 1 내지 2)이다.Wherein R 1 is a hydroxy group, methoxy group or methylsulfanyl group (m is 1 to 3), and R 2 is halogen (n is 1 to 2).
화학식 3Formula 3
상기 식에서, R1 및 R2는 각각 수소, 메톡시기, 메틸설파닐기 또는 할로겐이고, 다만 R1이 수소 또는 메톡시기일 경우 R2가 수소 또는 메톡시기인 경우는 제외한다.In the above formula, R 1 and R 2 are each hydrogen, methoxy group, methylsulfanyl group or halogen, except that when R 1 is hydrogen or methoxy group, R 2 is hydrogen or methoxy group.
본 발명에 따른 화학식 1 내지 3으로 표시되는 플라본 유도체는 또한 약학적으로 허용가능한 염을 형성할 수 있다. 이러한 약제학적으로 허용가능한 염에는 약제학적으로 허용가능한 음이온을 함유하는 무독성 산부가염을 형성하는 산, 예를들어 염산, 황산, 질산, 인산, 브롬화수소산, 요오드화수소산 등과 같은 무기산; 타르타르산, 포름산, 구연산, 초산, 트리클로로초산, 트리플루오로초산, 글루콘산, 벤조산, 락트산, 푸마르산, 말레인산 등과 같은 유기 카본산; 메탄설폰산, 벤젠설폰산, p-톨루엔설폰산 또는 나프탈렌설폰산 등과 같은 설폰산 등에 의해 형성된 산부가염이 포함된다.The flavone derivatives represented by Formulas 1 to 3 according to the present invention may also form pharmaceutically acceptable salts. Such pharmaceutically acceptable salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, and the like; Organic carbon acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, and the like; Acid addition salts formed by sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid and the like.
본 발명에 따른 화학식 1 내지 3으로 표시되는 플라본 유도체 또는 약학적으로 허용가능한 그의 염 중에서 대표적인 화합물로는 3',4'-디클로로-7-메톡시플라본, 2',4',7-트리메톡시플라본, 5,7-디히드록시-6,8-디브로모플라본 및 5,7-디히드록시-6,8-디메틸설파닐플라본으로 이루어진 군으로부터 선택된다.Representative compounds among the flavone derivatives represented by Formulas 1 to 3 or pharmaceutically acceptable salts thereof according to the present invention include 3 ', 4'-dichloro-7-methoxyflavone, 2', 4 ', 7-trimeth Oxyflavones, 5,7-dihydroxy-6,8-dibromoflavones and 5,7-dihydroxy-6,8-dimethylsulfanylflavones.
또한, 본 발명에 따른 화학식 1 내지 3으로 표시되는 플라본 유도체 또는 약학적으로 허용가능한 그의 염은 우수한 COX-2 및 iNOS의 발현 또는 활성 저해능력을 나타내므로, 본 발명은 화학식 1 내지 3으로 표시되는 플라본 유도체 또는 약학적으로 허용가능한 그의 염을 유효성분으로 함유하는 염증질환치료제용 약학적 조성물을 제공한다.In addition, the flavone derivatives represented by the formulas (1) to (3) or the pharmaceutically acceptable salts thereof according to the present invention exhibit excellent expression of COX-2 and iNOS or the ability to inhibit activity. It provides a pharmaceutical composition for treating inflammatory diseases containing a flavone derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 염증질환은 급성염증질환; 류마티스성 관절염 등의 만성염증질환; 및 건선 또는 아토피성 피부염 등의 피부염증질환인 것을 특징으로 한다.The inflammatory disease is an acute inflammatory disease; Chronic inflammatory diseases such as rheumatoid arthritis; And dermatitis diseases such as psoriasis or atopic dermatitis.
또한, 본 발명에 따른 화학식 1 내지 3으로 표시되는 플라본 유도체 또는 약학적으로 허용가능한 그의 염은 우수한 COX-2 및 iNOS의 발현 또는 활성 저해능력을 나타내므로, 본 발명은 화학식 1 내지 3으로 표시되는 플라본 유도체 또는 약학적으로 허용가능한 그의 염을 유효성분으로 함유하는 면역조절제용 약학적 조성물을 제공한다.In addition, the flavone derivatives represented by the formulas (1) to (3) or the pharmaceutically acceptable salts thereof according to the present invention exhibit excellent expression of COX-2 and iNOS or the ability to inhibit activity. It provides a pharmaceutical composition for immunomodulators containing a flavone derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 본 발명에 따른 화학식 1 내지 3으로 표시되는 플라본 유도체 또는 약학적으로 허용가능한 그의 염은 우수한 COX-2 및 iNOS의 발현 또는 활성 저해능력을 나타내므로, 본 발명은 화학식 1 내지 3으로 표시되는 플라본 유도체 또는 약학적으로 허용가능한 그의 염을 유효성분으로 함유하는 암질환 예방용 약학적 조성물을 제공한다.In addition, the flavone derivatives represented by the formulas (1) to (3) or the pharmaceutically acceptable salts thereof according to the present invention exhibit excellent expression of COX-2 and iNOS or the ability to inhibit activity. It provides a pharmaceutical composition for preventing cancer diseases containing a flavone derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
특히, 상기 암질환은 대장암인 것을 특징으로 한다.In particular, the cancer disease is characterized in that the colorectal cancer.
상기 약학적 조성물은 임상 투여시에 경구 또는 비경구로 투여가 가능하며 일반적인 의약품 제제의 형태로 사용될 수 있다. 바람직한 약제학적 제제는 정제, 경질 또는 연질 캅셀제, 액제, 현탁제 등과 같은 경구투여용 제제, 주사용 용액 또는 현탁액과 같은 비경구투여용 주사제 등이 있으며, 이들 약제학적 제제는 약제학적으로 허용 가능한 통상의 담체, 예를들어 경구투여용 제제의 경우에는 부형제, 결합제, 붕해제, 활택제, 가용화제, 현탁화제, 보존제 또는 증량제 등을, 주사제의 경우에는 안정화제, 보존제, 용해보조제, 완충제 또는 등장화제 등을 사용하여 조제할 수 있다. 투약 단위는, 예를들어 개별 투약량의 1, 2, 3 또는 4배를 함유하거나 또는 1/2, 1/3 또는 1/4배를 함유할 수 있다. 개별 투약량은 바람직하기로는 유효 약물이 1회에 투여되는 양을 함유하며, 이는 통상 1일 투여량의 전부, 1/2, 1/3 또는 1/4배에 해당한다.The pharmaceutical composition may be administered orally or parenterally during clinical administration and may be used in the form of a general pharmaceutical preparation. Preferred pharmaceutical preparations include tablets, hard or soft capsules, oral preparations such as liquids, suspensions, and parenteral injections such as injectable solutions or suspensions, and these pharmaceutical preparations are conventionally pharmaceutically acceptable. Carriers, for example, for oral preparations, excipients, binders, disintegrants, lubricants, solubilizers, suspending agents, preservatives or extenders, and in the case of injections, stabilizers, preservatives, dissolution aids, buffers or isotonic agents. A topical agent etc. can be used. Dosage units may, for example, contain 1, 2, 3 or 4 times the individual dosage or may contain 1/2, 1/3 or 1/4 times. The individual dosage preferably contains an amount in which the effective drug is administered at one time, which usually corresponds to all, 1/2, 1/3 or 1/4 times the daily dose.
상기 약학적 조성물에서, 본 발명에 따른 화학식 1 내지 3으로 표시되는 플라본 유도체 및 약학적으로 허용가능한 이들의 염의 유효용량은 0.1 내지 200 mg/kg 또는 피부적용시 0.1 내지 200 mg/cm2이고, 바람직하게는 10 내지 100 mg/kg 또는 피부적용시 1 내지 10 mg/cm2이며, 하루 1-6 회 투여될 수 있다. 단, 특정 환자에 대한 투여용량 수준은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설율, 질환의 중증도 등에 따라 변화될 수 있다.In the pharmaceutical composition, the effective dose of the flavone derivatives represented by Formulas 1 to 3 and pharmaceutically acceptable salts thereof according to the present invention is 0.1 to 200 mg / kg or 0.1 to 200 mg / cm 2 when applied to the skin, Preferably it is 10 to 100 mg / kg or 1 to 10 mg / cm 2 when applied skin, may be administered 1-6 times a day. However, the dosage level for a particular patient may vary depending on the weight, age, sex, health status, diet, time of administration, administration method, excretion rate, severity of the disease, and the like of the patient.
본 발명에 따른 화학식 1 내지 3으로 표시되는 플라본 유도체 및 약학적으로 허용가능한 이들의 염은 랫트에 경구 투여, 복강내 투여 및 피하 주사시의 독성 실험을 수행한 결과, 경구투여 독성시험에 의한 50% 치사량(LD50)은 500 mg/kg 이상인 것으로 확인되었고 따라서, 본 발명에 따른 화학식 1 내지 3으로 표시되는 플라본 유도체 및 약학적으로 허용가능한 이들의 염은 안전한 물질로 판명되었다.The flavone derivatives represented by Chemical Formulas 1 to 3 and pharmaceutically acceptable salts thereof according to the present invention were subjected to oral toxicity, intraperitoneal administration, and subcutaneous injection in rats. The% lethal dose (LD 50 ) was found to be 500 mg / kg or more, and therefore the flavone derivatives represented by the formulas (1) to (3) and the pharmaceutically acceptable salts thereof according to the present invention were found to be safe substances.
이하에서는 본 발명을 실시예에 의하여 보다 상세하게 설명한다. 그러나, 하기의 실시예는 본 발명을 설명하기 위하여 제시되는 것이며, 본 발명의 범위를 제한하기 위한 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following examples are presented to illustrate the present invention and are not intended to limit the scope of the present invention.
<실시예 1><Example 1>
2,4,6-트리히드록시아세토페논 1.26 g, 탄산칼륨 1.50 g을 아세톤 10 mL와 혼합하고, 교반하면서 디메틸설페이트 1.89 g을 약 10분에 걸쳐 서서히 가한 후 4시간동안 가열 환류하였다. 반응액을 냉각하고 탄산칼륨을 여과한 후, 여액을 150 mL의 냉수에 가하여 석출되는 고체를 여과하고 메탄올에서 재결정하여 90%의 수율로 무색의 2-히드록시-4,6-디메톡시아세토페논 고체를 얻었다. 2,4-, 2,5-, 2,6-디히드록시아세토페논들을 동일조건에서 반응하면 각각에 해당하는 2-히드록시 상태의 메톡시아세토페논들을 얻을 수 있다.1.26 g of 2,4,6-trihydroxyacetophenone and 1.50 g of potassium carbonate were mixed with 10 mL of acetone, and 1.89 g of dimethylsulfate was slowly added over about 10 minutes while stirring, followed by heating to reflux for 4 hours. After cooling the reaction solution and filtering potassium carbonate, the filtrate was added to 150 mL of cold water, and the precipitated solid was filtered and recrystallized from methanol to yield a colorless 2-hydroxy-4,6-dimethoxyacetophenone in 90% yield. A solid was obtained. When 2,4-, 2,5-, 2,6-dihydroxyacetophenones are reacted under the same conditions, methoxyacetophenones of the corresponding 2-hydroxy state can be obtained.
2-히드록시-4,6-디메톡시아세토페논 980 mg과 3,4-디클로로벤즈알데히드 865 mg을 메탄올 5 mL에 용해시키고 수산화칼륨 860 mg을 가하여 실온에서 6시간 교반하였다. 반응액을 냉수 100 mL에 부은 후, 진한 염산수용액을 가하여 액성을 산성으로 조절하면 황색의 고체가 침전된다. 고체를 여과하고 메탄올 용매에서 재결정하면 82% 수율로 정제된 3,4-디클로로-4',6'-디메톡시-2'-히드록시찰콘을 얻을 수 있다. 2,4-, 2,5-, 2,6-디히드록시아세토페논들을 동일조건에서 반응하면 각각에 해당하는 생성물을 얻을 수 있다. 또한, 다양한 치환기를 갖는 벤즈알데히드들을 동일조건에서 반응시켜 다양한 치환기를 갖는 2'-히드록시메톡시찰콘을 마찬가지로 얻을 수 있다.980 mg of 2-hydroxy-4,6-dimethoxyacetophenone and 865 mg of 3,4-dichlorobenzaldehyde were dissolved in 5 mL of methanol, 860 mg of potassium hydroxide was added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was poured into 100 mL of cold water, and then concentrated aqueous hydrochloric acid solution was added to make the liquid acidic. A yellow solid precipitated out. Filtration of the solid and recrystallization in methanol solvent afforded 3,4-dichloro-4 ', 6'-dimethoxy-2'-hydroxychalcone purified in 82% yield. When the 2,4-, 2,5-, 2,6-dihydroxyacetophenones are reacted under the same conditions, corresponding products can be obtained. In addition, benzaldehydes having various substituents can be reacted under the same conditions to obtain 2'-hydroxymethoxychalcones having various substituents as well.
3,4-디클로로-4',6'-디메톡시-2'-히드록시찰콘 1.81 g을 디메틸설폭사이드 10 mL에 용해시키고 촉매량의 요오드를 가하고 용액을 4시간 가열 후 실온으로 냉각시킨 다음, 수용성 티오황산나트륨 포화수용액 10 mL에 가하고 침전하는 고체를 여과하여 디클로로메탄-메탄올 혼합용액에서 재결정하여 70% 수율로 무색 고체 상태의 3',4'-디클로로-5,7-디메톡시를 얻었다.1.81 g of 3,4-dichloro-4 ', 6'-dimethoxy-2'-hydroxychalcone was dissolved in 10 mL of dimethylsulfoxide, a catalytic amount of iodine was added, the solution was heated for 4 hours, then cooled to room temperature, To 10 mL of saturated aqueous sodium thiosulfate solution was added, and the precipitated solid was filtered and recrystallized from a dichloromethane-methanol mixed solution to obtain 3 ', 4'-dichloro-5,7-dimethoxy as a colorless solid in 70% yield.
3',4'-디클로로-5,7-디메톡시플라본을 AlCl3와 반응시키면 선택적으로 5-메톡시의 메틸기를 제거하여 3',4'-디클로로-5-히드록시-7-메톡시플라본을 얻을 수 있었다. 기타 관련화합물도 동일조건에서 5번의 탈메틸화에 의해 목적하는 5-히드록시플라본들을 얻을 수 있었다. 한편, BBr3(브로모보론)시약을 작용하여 5번 및 7번 위치의 탈메틸화를 동시에 진행시킴으로써 3',4'-디클로로-5,7-디히드록시플라본을 얻을 수 있었다. 한편, BBr3 시약을 작용하여 5,6,7 및 8번 위치의 탈메틸화를 진행시킴으로써 다양한 (폴리)히드록시플라본들을 얻을 수 있었다.Reaction of 3 ', 4'-dichloro-5,7-dimethoxyflavone with AlCl 3 selectively removes the methyl group of 5-methoxy to give 3', 4'-dichloro-5-hydroxy-7-methoxyflavone Could get Other related compounds were able to obtain the desired 5-hydroxyflavones by demethylation five times under the same conditions. On the other hand, BBr 3 by reaction with (bromo-boron) reagent proceeds by the demethylation of 5 and at position 7 could be obtained at the same time the 3 ', 4'-dichloro-5,7-dihydroxy-flavone. On the other hand, various (poly) hydroxyflavones could be obtained by demethylation at positions 5, 6, 7, and 8 by acting with the BBr 3 reagent.
<실시예 2><Example 2>
크리신(Chrysin; 5,7-디히드록시플라본) 1.27 g, 탄산칼륨 1.60 g과 아세톤 15 mL에 현탁 후, 교반하면서 디메틸설페이트 1.94 g을 서서히 가하고 6시간동안 가열환류하였다. 반응액을 냉각하고 탄산칼륨을 여과한 후 여액을 200 mL의 냉수에 가하여 석출되는 고체를 여과하고 메탄올에서 재결정하여 88%의 수율로 무색의 5,7-디메톡시플라본 고체를 얻었다. 5,7-디메톡시플라본 1.41 g을 초산 30 mL 및 아세톤 5 mL에 요오드 1.26 g을 용해한 용액과 혼합 후, 실온에서 20분간 교반하고 5 mL의 초산에 70% 질산 0.5 mL을 혼합한 액을 서서히 적하하였다. 석출하는 고체를 여과하고 10% 티오황산나트륨 수용액 및 물로 세척하고 아세톤 용매를 이용하여 재결정하면 78% 수율로 6,8-디아이오도-5,7-디메톡시플라본을 얻었다. 생성물을 AlCl3와 반응시켜 선택적으로 5-메톡시의 메틸기를 제거함으로써 5-히드록시-6,8-디아이오도-7-디메톡시플라본을 얻을 수 있었다. 한편, BBr3 시약을 작용하여 5번 및 7번 위치의 탈메틸화를 동시에 진행함으로써 5,7-디히드록시-6,8-디아이오도플라본을 얻을 수 있었다. 요오드 대신에 당량에 해당하는 브롬을 사용하고 동일한 과정을 거치면 각각 6,8-디브로모-5,7-디메톡시플라본, 6,8-디브로모-5-히드록시-7-메톡시플라본 및 6.8-디브로모-5,7-디히드록시플라본을 얻을 수 있었다.1.27 g of Chrysin (5,7-dihydroxyflavone), 1.60 g of potassium carbonate and 15 mL of acetone were suspended, and then 1.94 g of dimethyl sulfate was slowly added while stirring, followed by heating under reflux for 6 hours. After cooling the reaction solution and filtering potassium carbonate, the filtrate was added to 200 mL of cold water, and the precipitated solid was filtered and recrystallized from methanol to give a colorless 5,7-dimethoxyflavone solid in 88% yield. After mixing 1.41 g of 5,7-dimethoxyflavone with 30 mL of acetic acid and a solution of 1.26 g of iodine in 5 mL of acetone, the mixture was stirred at room temperature for 20 minutes and 0.5 mL of 70% nitric acid was mixed with 5 mL of acetic acid. It dripped. The precipitated solid was filtered, washed with 10% aqueous sodium thiosulfate solution and water and recrystallized with acetone solvent to give 6,8-dioodo-5,7-dimethoxyflavone in 78% yield. The product was reacted with AlCl 3 to selectively remove the 5-methoxy methyl group, yielding 5-hydroxy-6,8-dioodo-7-dimethoxyflavone. On the other hand, by the action of BBr 3 reagent was obtained 5,7-dihydroxy-6, 8-DI Goto flavone by a demethylation proceeds in the 5 and 7-position simultaneously. Using the equivalent bromine instead of iodine and following the same procedure, 6,8-dibromo-5,7-dimethoxyflavone, 6,8-dibromo-5-hydroxy-7-methoxyflavone, respectively And 6.8-dibromo-5,7-dihydroxyflavones.
<실시예 3><Example 3>
크리신(Chrysin) 1.27 g에 0.8 g의 AlCl3, 1.33 mL의 디메틸디설파이드 및 톨루엔 10 mL을 가한 후 100oC에서 15시간 가열하였다. 반응 온도를 40oC로 냉각하고 4 N-HCl 수용액 10 mL을 가하여 가수분해한 후, 디클로르메탄 10 mL로 5회 추출하고 추출액을 감압증류하여 유기용매를 제거하였다. 얻어진 조생성물을 칼럼크로마토그라피를 통하여 분리정제하여 34% 수율로서 무색의 고체인 5,7-디히드록시-6,8-디메틸설파닐플라본을 얻었다.To 1.27 g of Chrysin, 0.8 g of AlCl 3 , 1.33 mL of dimethyl disulfide and 10 mL of toluene were added, followed by heating at 100 ° C. for 15 hours. The reaction temperature was cooled to 40 ° C., hydrolyzed by adding 10 mL of 4 N-HCl aqueous solution, and extracted five times with 10 mL of dichloromethane, and the extract was distilled under reduced pressure to remove the organic solvent. The obtained crude product was separated and purified through column chromatography to obtain 5,7-dihydroxy-6,8-dimethylsulfanyl flavone as a colorless solid in 34% yield.
1) 4'-브로모플라본1) 4'-bromoflavones
1H-NMR (200MHz, CDCl3): 8.23(1H, q, H5), 7.83(2H, d, H3, H5), 7.73∼7.41(5H, m, H2, H6, H5, H6, H7, H8), 6.82(1H, s, H3). 1 H-NMR (200 MHz, CDCl 3 ): 8.23 (1H, q, H5), 7.83 (2H, d, H3, H5), 7.73-7.41 (5H, m, H2, H6, H5, H6, H7, H8 ), 6.82 (1H, s, H3).
2) 4'-클로로플라본2) 4'-chloroflavones
1H-NMR (200MHz, CDCl3): 8.24(1H, q, H5), 7.88(2H, d, H3, H5), 7.77∼7.41(5H, m, H2, H5, H6, H7, H8), 6.81(1H, s, H3). 1 H-NMR (200 MHz, CDCl 3 ): 8.24 (1H, q, H5), 7.88 (2H, d, H3, H5), 7.77-7.41 (5H, m, H2, H5, H6, H7, H8), 6.81 (1 H, s, H 3).
3) 3',4'-디클로로플라본3) 3 ', 4'-dichloroflavones
1H-NMR (200MHz, CDCl3): 8.24(1H, q, H5), 8.05(1H, d, H2), 7.78∼7.43(5H, m, H3, H5, H6, H7, H8), 6.80(1H, s, H3). 1 H-NMR (200 MHz, CDCl 3 ): 8.24 (1H, q, H5), 8.05 (1H, d, H2), 7.78-7.43 (5H, m, H3, H5, H6, H7, H8), 6.80 ( 1H, s, H3).
4) 3',4'-디히드록시플라본4) 3 ', 4'-dihydroxyflavones
1H-NMR (200MHz, DMSO-d6): 9.04(1H, s, OH), 8.678(1H, s, OH), 8.19∼7.36(6H, m, H3, H5, H6, H7, H8), 6.82(1H, d, H5), 6.67(1H, s, H2). 1 H-NMR (200 MHz, DMSO-d 6 ): 9.04 (1H, s, OH), 8.678 (1H, s, OH), 8.19-7.36 (6H, m, H3, H5, H6, H7, H8), 6.82 (1H, d, H5), 6.67 (1H, s, H2).
5) 2',3'-디메톡시플라본5) 2 ', 3'-dimethoxyflavones
1H-NMR (200MHz, CDCl3): 8.26(1H, q, H5), 7.83(1H, q, H7), 7.52∼6.97(6H, m, H4, H5, H6, H3, H8), 3.92(6H, s, OCH3). 1 H-NMR (200 MHz, CDCl 3 ): 8.26 (1H, q, H5), 7.83 (1H, q, H7), 7.52-6.97 (6H, m, H4, H5, H6, H3, H8), 3.92 ( 6H, s, OCH 3).
6) 3',4'-디메톡시플라본6) 3 ', 4'-dimethoxyflavones
1H-NMR (200MHz, CDCl3): 8.23(1H, q, H5), 7.69(1H, q, H7), 7.60∼7.40(5H, m, H2, H5, H6, H8), 6.78(1H, s, H3), 3.98(6H, s, OCH3). 1 H-NMR (200 MHz, CDCl 3 ): 8.23 (1H, q, H5), 7.69 (1H, q, H7), 7.60-7.40 (5H, m, H2, H5, H6, H8), 6.78 (1H, s, H 3), 3.98 (6H, s, OCH 3).
7) 2',4'-디메톡시플라본7) 2 ', 4'-dimethoxyflavones
1H-NMR (200MHz, CDCl3): 8.25(1H, d, H5), 7.91(1H, d, H7), 7.70∼7.15(3H, m, H6, H8), 7.15(1H, s, H3), 6.64(1H, d, H5), 6.57(1H, s, H3), 3.92(6H, s, OCH3). 1 H-NMR (200 MHz, CDCl 3 ): 8.25 (1H, d, H5), 7.91 (1H, d, H7), 7.70-7.71 (3H, m, H6, H8), 7.15 (1H, s, H3) , 6.64 (1H, d, H5), 6.57 (1H, s, H3), 3.92 (6H, s, OCH3).
8) 2',3',4'-트리메톡시플라본8) 2 ', 3', 4'-trimethoxyflavone
1H-NMR (200MHz, CDCl3): 8.23(1H, q, H5), 7.37∼7.37(4H, m, H6, H7, H8), 7.00 (1H, s, H3), 6.837∼6.791(1H, d, H5), 3.94(9H, s, OCH3). 1 H-NMR (200 MHz, CDCl 3 ): 8.23 (1H, q, H5), 7.37-7.37 (4H, m, H6, H7, H8), 7.00 (1H, s, H3), 6.837-6.791 (1H, d, H 5), 3.94 (9H, s, OCH 3).
9) 4'-메틸-7-메톡시플라본9) 4'-methyl-7-methoxyflavone
1H-NMR (200MHz, CDCl3): 8.149(1H, d, H5), 7.82(2H, d, H2, H6), 7.32(2H, d, H3, H5), 6.91∼6.97(2H, m, H3, H6), 6.75(1H, s, H8), 3.94(3H, s, OCH3), 2.45(3H, s, CH3). 1 H-NMR (200 MHz, CDCl 3 ): 8.149 (1H, d, H5), 7.82 (2H, d, H2, H6), 7.32 (2H, d, H3, H5), 6.91-6.97 (2H, m, H3, H6), 6.75 (1H, s, H8), 3.94 (3H, s, OCH3), 2.45 (3H, s, CH3).
10) 3',4'-디클로로-7-메톡시플라본10) 3 ', 4'-dichloro-7-methoxyflavone
1H-NMR (200MHz, CDCl3): 8.14(1H, d, H5), 8.03(1H, d, H2), 7.72(1H, q, H5), 7.60(1H, d, H6), 6.99(1H, s, H3), 6.74(1H, s, H8), 3.95(3H, s, OCH3). 1 H-NMR (200 MHz, CDCl 3 ): 8.14 (1H, d, H5), 8.03 (1H, d, H2), 7.72 (1H, q, H5), 7.60 (1H, d, H6), 6.99 (1H , s, H3), 6.74 (1H, s, H8), 3.95 (3H, s, OCH3).
11) 4'-히드록시-7-메톡시플라본11) 4'-hydroxy-7-methoxyflavone
1H-NMR (200MHz, DMSO-d6): 9.78(1H, s, OH), 8.07(1H, d, H5), 7.79(2H, d, H2, H6), 7.01∼6.96(4H, m, H3, H5, H6), 6.73(1H, s, H8), 3.96(3H, s, OCH3). 1 H-NMR (200 MHz, DMSO-d 6 ): 9.78 (1H, s, OH), 8.07 (1H, d, H5), 7.79 (2H, d, H2, H6), 7.01-6.96 (4H, m, H3, H5, H6), 6.73 (1H, s, H8), 3.96 (3H, s, OCH3).
12) 2',3',7-트리메톡시플라본12) 2 ', 3', 7-trimethoxyflavone
1H-NMR (200MHz, CDCl3): 8.23(1H, d, H5), 7.77(1H, d, H6), 7.33∼6.91(5H, m, H4, H5, H3, H6, H8), 3.90(9H, s, OCH3). 1 H-NMR (200 MHz, CDCl 3 ): 8.23 (1H, d, H5), 7.77 (1H, d, H6), 7.33-6.61 (5H, m, H4, H5, H3, H6, H8), 3.90 ( 9H, s, OCH 3).
13) 2',4',7-트리메톡시플라본13) 2 ', 4', 7-trimethoxyflavone
1H-NMR (200MHz, CDCl3): 8.13(1H, d, H5), 7.88(1H, d, H6), 7.07(1H, d, H6), 6.96(2H, q, H3, H6), 6.62(1H, d, H5), 6.56(1H, s, H3), 3.91(9H, s, OCH3). 1 H-NMR (200 MHz, CDCl 3 ): 8.13 (1H, d, H5), 7.88 (1H, d, H6), 7.07 (1H, d, H6), 6.96 (2H, q, H3, H6), 6.62 (1H, d, H5), 6.56 (1H, s, H3), 3.91 (9H, s, OCH3).
14) 3',4',5',7-테트라메톡시플라본14) 3 ', 4', 5 ', 7-tetramethoxyflavone
1H-NMR (200MHz, CDCl3): 8.15(1H, q, H5), 7.12(2H, s, H2, H6), 7.04(1H, s, H3), 6.99(1H, s, H6), 6.72(1H, s, H8), 3.95(12H, s, OCH3). 1 H-NMR (200 MHz, CDCl 3 ): 8.15 (1H, q, H5), 7.12 (2H, s, H2, H6), 7.04 (1H, s, H3), 6.99 (1H, s, H6), 6.72 (1H, s, H8), 3.95 (12H, s, OCH3).
15) 4'-브로모-5,7-디메톡시플라본15) 4'-bromo-5,7-dimethoxyflavone
1H-NMR (200MHz, CDCl3): 7.64(4H, m, H2, H3, H5, H6), 6.66(1H, s, H3), 6.56(1H, s, H6), 6.40(1H, s, H8), 3.94(6H, s, OCH3). 1 H-NMR (200 MHz, CDCl 3 ): 7.64 (4H, m, H 2, H 3 , H 5, H 6), 6.66 (1 H, s, H 3), 6.56 (1 H, s, H 6), 6.40 (1 H, s, H 8), 3.94 (6H, s, OCH 3).
16) 3',4'-디클로로-5,7-디메톡시플라본16) 3 ', 4'-dichloro-5,7-dimethoxyflavone
1H-NMR (200MHz, CDCl3): 7.98(1H, d, H2),7.71∼7.55(2H, m, H5, H6), 6.65(1H, s, H3), 6.58(1H, d, H6), 6.40(1H, d, H8), 3.94(6H, s, OCH3). 1 H-NMR (200 MHz, CDCl 3 ): 7.98 (1H, d, H2), 7.71-7.75 (2H, m, H5, H6), 6.65 (1H, s, H3), 6.58 (1H, d, H6) , 6.40 (1H, d, H 8), 3.94 (6H, s, OCH 3).
17) 2',4',5,7-테트라메톡시플라본17) 2 ', 4', 5,7-tetramethoxyflavone
1H-NMR (200MHz, CDCl3): 7.85(1H, d, H6), 6.64∼6.52(4H, m, H3, H5, H8), 6.36(1H, d, H8), 3.92(12H, s, OCH3). 1 H-NMR (200 MHz, CDCl 3 ): 7.85 (1H, d, H6), 6.64-6.52 (4H, m, H3, H5, H8), 6.36 (1H, d, H8), 3.92 (12H, s, OCH3).
18) 5,7-디메톡시-6,8-디아이오도플라본18) 5,7-dimethoxy-6,8-dioodoflavones
1H-NMR (200MHz, CDCl3): 8.07(2H, d, H2, H6), 7.58∼7.57(3H, m, H3, H4, H5), 6.80(1H, s, H3), 3.97(6H, s, OCH3). 1 H-NMR (200 MHz, CDCl 3 ): 8.07 (2H, d, H2, H6), 7.58-7.7.5 (3H, m, H3, H4, H5), 6.80 (1H, s, H3), 3.97 (6H, s, OCH 3).
19) 4'-브로모-5-메톡시플라본19) 4'-bromo-5-methoxyflavone
1H-NMR (200MHz, CDCl3): 8.06(1H, t, H7), 7.17∼7.13(4H, m, H3, H4, H5, H6), 7.15(1H, d, H3), 6.85(1H, d, H6), 6.72(1H, s, H8), 4.01(3H, s, OCH3). 1 H-NMR (200 MHz, CDCl 3 ): 8.06 (1H, t, H7), 7.17-7.13 (4H, m, H3, H4, H5, H6), 7.15 (1H, d, H3), 6.85 (1H, d, H6), 6.72 (1H, s, H8), 4.01 (3H, s, OCH3).
20) 3',4',5,7-테트라히드록시플라본20) 3 ', 4', 5,7-tetrahydroxyflavones
1H-NMR (200MHz, DMSO-d6): 12.87(1H, s, OH), 10.86(1H, s, OH), 10.02(1H, s, OH), 9.63(1H, s, OH), 7.32∼6.20(6H, m, H2, H5, H3, H6, H8). 1 H-NMR (200 MHz, DMSO-d 6 ): 12.87 (1H, s, OH), 10.86 (1H, s, OH), 10.02 (1H, s, OH), 9.63 (1H, s, OH), 7.32 -6.20 (6H, m, H2, H5, H3, H6, H8).
21) 3',4'-디클로로-5,7-디히드록시플라본21) 3 ', 4'-dichloro-5,7-dihydroxyflavone
1H-NMR (200MHz, DMSO-d6): 8.35(1H, d, H2), 8.05(1H, q, H5), 7.83(1, d, H6), 7.01(1H, s, H3), 6,42(2H, d, H6, H8). 1 H-NMR (200 MHz, DMSO-d 6 ): 8.35 (1H, d, H2), 8.05 (1H, q, H5), 7.83 (1, d, H6), 7.01 (1H, s, H3), 6 , 42 (2H, d, H6, H8).
22) 5,7-디히드록시-6,8-디브로모플라본22) 5,7-dihydroxy-6,8-dibromoflavone
1H-NMR (200MHz, DMSO-d6): 13.689(1H, s, OH), 8.07(2H, t, H2, H6), 7.93(1H, s, OH), 7.59(3H, t, H3, H4, H5), 6.95(1H, s, H3). 1 H-NMR (200 MHz, DMSO-d 6 ): 13.689 (1H, s, OH), 8.07 (2H, t, H2, H6), 7.93 (1H, s, OH), 7.59 (3H, t, H3, H4, H5), 6.95 (1H, s, H3).
23) 5,7-디히드록시-6,8-디메틸설파닐플라본23) 5,7-dihydroxy-6,8-dimethylsulfanylflavone
1H-NMR (200MHz, DMSO-d6): 8.04(2H, q, H2, H6), 7.59(3H, t, H3, H4, H5), 6.79(1H, s, H3), 2.40(6H, d, SCH3). 1 H-NMR (200 MHz, DMSO-d 6 ): 8.04 (2H, q, H2, H6), 7.59 (3H, t, H3, H4, H5), 6.79 (1H, s, H3), 2.40 (6H, d, SCH3).
24) 3',4',5-트리히드록시-7-메톡시플라본24) 3 ', 4', 5-trihydroxy-7-methoxyflavone
1H-NMR (200MHz, DMSO-d6): 12.99(1H, s, OH), 7.4749~6.3739(6H, m, H2, H5, H6, H3, H8), 3.87(3H, s, OCH3). 1 H-NMR (200 MHz, DMSO-d 6 ): 12.99 (1H, s, OH), 7.4749-6.3739 (6H, m, H2, H5, H6, H3, H8), 3.87 (3H, s, OCH3).
25) 3',4',5',7-테트라메톡시-5-히드록시플라본25) 3 ', 4', 5 ', 7-tetramethoxy-5-hydroxyflavone
1H-NMR (200MHz, DMSO-d6): 12.74(1H, s, OH), 7.09~6.40(5H, m, H2, H6, H3, H8), 3.95(12H, s, OCH3). 1 H-NMR (200 MHz, DMSO-d 6 ): 12.74 (1H, s, OH), 7.09-6.40 (5H, m, H2, H6, H3, H8), 3.95 (12H, s, OCH3).
26) 5,7-디히드록시-6,8-디아이오도플라본26) 5,7-dihydroxy-6,8-dioodoflavones
1H-NMR (200MHz, DMSO-d6): 14.02(1H, s, OH), 8.25~8.22(2H, m, H2, H6), 7.66∼7.63(3H, m, H3, H4) 1 H-NMR (200 MHz, DMSO-d 6 ): 14.02 (1H, s, OH), 8.25-8.22 (2H, m, H2, H6), 7.66-7.63 (3H, m, H3, H4)
27) 5-메톡시-7-히드록시플라본27) 5-methoxy-7-hydroxyflavone
1H-NMR (200MHz, DMSO-d6): 10.36(1H, s, OH), 7.92(2H, d, H2, H6), 7.54∼7.51(3H, m, H3, H4, H5), 6.54(2H, d, H6, H8), 3.88(3H, s, OCH3). 1 H-NMR (200 MHz, DMSO-d 6 ): 10.36 (1H, s, OH), 7.92 (2H, d, H2, H6), 7.54-7.51 (3H, m, H3, H4, H5), 6.54 ( 2H, d, H6, H8), 3.88 (3H, s, OCH3).
28) 3'-브로모-7-히드록시플라본28) 3'-bromo-7-hydroxyflavone
1H-NMR (200MHz, DMSO-d6): 8.07(1H, t, H5), 7.85~6.72(7H, m, H2, H3, H5, H6, H8). 1 H-NMR (200 MHz, DMSO-d 6 ): 8.07 (1H, t, H5), 7.85-6.72 (7H, m, H2, H3, H5, H6, H8).
29) 4'-브로모-7-히드록시플라본29) 4'-bromo-7-hydroxyflavone
1H-NMR (200MHz, DMSO-d6): 8.04(1H, t, H5), 7.84~7.32(4H, m, H2, H3, H5, H6), 6.56(1H, s, H3), 6.33(1H, q, H6), 6.10(1H, d, H8). 1 H-NMR (200 MHz, DMSO-d 6 ): 8.04 (1H, t, H5), 7.84-7.32 (4H, m, H2, H3, H5, H6), 6.56 (1H, s, H3), 6.33 ( 1H, q, H6), 6.10 (1H, d, H8).
30) 3',4',5',7-테트라히드록시플라본30) 3 ', 4', 5 ', 7-tetrahydroxyflavones
1H-NMR (200MHz, DMSO-d6): 7.86(1H, t, H5), 6.95~6.47(5H, m, H2, H3, H6, H8). 1 H-NMR (200 MHz, DMSO-d 6 ): 7.86 (1H, t, H5), 6.95-6.67 (5H, m, H2, H3, H6, H8).
<실시예 4><Example 4>
실시예 1 내지 3에서 합성된 유도체들의 COX-2에 대한 영향을 검정하기 위하여 Chi등의 방법(Biochemical Pharmacology 61, 1195, 2001)에 따라 실험하였다. 즉, RAW 264.7 세포주를 1 ㎍/ml 농도의 리포폴리사카로이드(lipopolysaccharide, 이하 "LPS"라고 약칭함)로 처리하여 COX-2를 발현시키고, 생성된 PGE2의 양을 ELISA법으로 검정하였다. 이때 각 유도체 10μM의 농도를 동시에 처리하고 24시간 배양하였다. 그 결과는 하기의 표 1과 같다. 또한, 세포독성은 Mossman의 방법(J. Immunological Methods 65, 55, 1983)을 이용하여 MTT법으로 검정하였다. 세포독성 검정 결과, 모든 유도체들은 검정농도인 10 μM에서 어떠한 세포독성도 나타나지 않았다.In order to test the effects of the derivatives synthesized in Examples 1 to 3 on COX-2, experiments were conducted according to Chi et al. ( Biochemical Pharmacology 61, 1195, 2001). That is, the RAW 264.7 cell line was treated with lipopolysaccharide (lipopolysaccharide, hereinafter abbreviated as "LPS") at a concentration of 1 µg / ml to express COX-2, and the amount of PGE 2 generated was assayed by ELISA method. At this time, the concentration of each derivative 10μM was treated simultaneously and incubated for 24 hours. The results are shown in Table 1 below. In addition, cytotoxicity was assayed by MTT method using Mossman's method ( J. Immunological Methods 65, 55, 1983). As a result of the cytotoxicity assay, all derivatives showed no cytotoxicity at the assay concentration of 10 μM.
<표 1>TABLE 1
<실시예 5>Example 5
실시예 4에서 강한 PGE2 저해 활성을 나타낸 플라본 유도체 중에서 2',4',7-트리메톡시플라본, 3',4'-디클로로-7-메톡시플라본 및 5,7-디히드록시-6,8-디메틸설파닐플라본에 대한 IC50 값을 구하였고, 본 발명에 따른 유도체의 IC50 값과 비교하기 위해 COX-2에 대한 강력하고 선택적인 저해제로 일반적으로 알려져 있는 NS-398(N-[2-시클로헥실옥시-4-니트로페닐]메탄 설폰아미드) 및 우고닌(wogonin, 5,7-디히드록시-8-메톡시플라본)을 양성 대조물질로 이용하였다.2 ', 4', 7-trimethoxyflavone, 3 ', 4'-dichloro-7-methoxyflavone and 5,7-dihydroxy-6 in flavone derivatives showing strong PGE 2 inhibitory activity in Example 4 IC 50 values for, 8-dimethylsulfanylflavones were obtained, and NS-398 (N-, commonly known as a potent and selective inhibitor of COX-2 for comparison with the IC 50 values of derivatives according to the present invention). [2-cyclohexyloxy-4-nitrophenyl] methane sulfonamide) and wogonin (5,7-dihydroxy-8-methoxyflavone) were used as positive controls.
다양한 농도에서 실험한 결과는 하기 도 1과 같고, 본 발명에 따른 유도체들이 양성 대조물질로 이용한 우고닌보다 더 낮은 IC50 값을 나타내어 뛰어난 PGE2 생성저해능을 보였다.Experimental results at various concentrations are as shown in Figure 1, the derivatives according to the present invention showed a lower IC 50 value than the ugonin used as a positive control showed excellent PGE 2 inhibitory ability.
<실시예 6><Example 6>
실시예 4에서 강한 PGE2 저해 활성을 나타낸 플라본 유도체 중에서 2',4',7-트리메톡시플라본 및 3',4'-디클로로-7-메톡시플라본의 COX-2에 대한 직접적인 발현 억제력은 웨스턴 블롯(Western blot)법으로 검정하였다. 그 결과는 도 2와 같고, 이들 유도체들은 COX-2의 발현을 억제하여 PGE2의 생성을 억제하는 것으로 판단되었다.Direct expression inhibition of 2 ', 4', 7-trimethoxyflavone and 3 ', 4'-dichloro-7-methoxyflavone to COX-2 in flavone derivatives showing strong PGE 2 inhibitory activity in Example 4 The assay was performed by Western blot method. The results are shown in Figure 2, these derivatives were determined to inhibit the production of PGE 2 by inhibiting the expression of COX-2.
또한, COX-2에 대한 직접적인 저해능을 검정하기 위하여 RAW 세포주를 LPS 존재하에서 24시간 배양하여 COX-2를 발현시키고, 완전히 세척한 후 AA를 첨가하고 30분간 반응시킨 후, 배지의 PGE2의 양을 정량하였고, 본 발명에 따른 유도체들의 COX-2에 대한 직접적인 저해능과 비교하기 위해 COX-2 저해제로 일반적으로 알려져 있는 NS-398 및 우고닌을 양성 대조물질로 이용하였다.In addition, in order to assay direct inhibition of COX-2, the RAW cell line was incubated for 24 hours in the presence of LPS to express COX-2, and after washing thoroughly, adding AA and reacting for 30 minutes, the amount of PGE 2 in the medium In order to compare the derivatives according to the present invention with direct inhibition of COX-2, NS-398 and ugonin, commonly known as COX-2 inhibitors, were used as positive controls.
그 결과는 표 2와 같고, 따라서 이들 유도체들은 COX-2의 발현을 억제할 뿐만 아니라, COX-2의 활성을 직접적으로 저해하는 작용도 지니고 있었다.The results are shown in Table 2, and therefore these derivatives not only inhibited the expression of COX-2, but also directly inhibited the activity of COX-2.
<표 2>TABLE 2
<실시예 7><Example 7>
실시예 4에서 강한 PGE2 저해 활성을 나타낸 플라본 유도체 중에서 2',4',7-트리메톡시플라본 및 3',4'-디클로로-7-메톡시플라본의 iNOS에 의한 NO의 생성억제능을 검토하였고, 본 발명에 따른 유도체의 NO 생성억제능과 비교하기 위해 강력하고 선택적인 iNOS 저해제인 AMT(2-아미노-5,6-디히드로-6-메틸-4H-1,3-티아진 염화수소) 및 우고닌을 양성 대조물질로 이용하였다. 즉, LPS가 처리된 RAW 264.7세포에서 Kim 등의 방법(Biochemical Pharmacology 58, 759, 1999)에 따라 실험하였고, 그 결과는 하기의 표 3과 같다. 또한, 웨스턴 블롯법으로 iNOS 유도 저해능을 측정한 결과는 도 4와 같다.In Example 4, 2 ', 4', 7-trimethoxyflavone and 3 ', 4'-dichloro-7-methoxyflavone were inhibited by iNOS of flavone derivatives showing strong PGE 2 inhibitory activity. AMT (2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine hydrogen chloride), a potent and selective iNOS inhibitor, for comparison with the NO production inhibitory activity of the derivatives according to the invention, and Ugonin was used as a positive control. That is, experiments were performed according to the method of Kim et al. ( Biochemical Pharmacology 58, 759, 1999) in LPS-treated RAW 264.7 cells, and the results are shown in Table 3 below. In addition, the results of measuring iNOS induction inhibition by Western blot method is shown in FIG.
따라서, 이들 유도체들은 50 μM 이상의 농도에서 NO의 생성을 저해하며, 이는 iNOS 발현 억제에 의한 것임을 알 수 있었다.Therefore, these derivatives inhibit the production of NO at a concentration of 50 μM or more, it was found that this is due to the inhibition of iNOS expression.
<표 3>TABLE 3
<실시예 8><Example 8>
실시예 4에서 강한 PGE2 저해 활성을 나타낸 플라본 유도체 중에서 2',4',7-트리메톡시플라본 및 3',4'-디클로로-7-메톡시플라본을 대상으로 하여 동물실험을 통한 염증억제력을 검정하기 위하여 TPA-유도 마우스 귀부종법을 이용하였고, 본 발명에 따른 유도체의 항염증작용과 비교하기 위해 항염증제로 널리 사용되고 있는 프레드니솔론(prednisolone), 우고닌 및 플라바논(flavanone)을 양성 대조물질로 이용하였다. 즉, TPA(3 ㎍/ear)를 하루에 한번씩 3일간 도포하였고, 본 발명에 따른 유도체들 및 양성 대조물질들은 마우스의 귀에 TPA 처리 2시간 및 12시간 후에 각각 발라서 3일 연속 피부적용하였고, 첫 TPA 처리 후의 경과된 시간을 36시간, 48시간 및 52시간으로 나누어 항염증활성을 검토하였다.Inflammation inhibitory activity through animal experiments targeting 2 ', 4', 7-trimethoxyflavone and 3 ', 4'-dichloro-7-methoxyflavone among flavone derivatives showing strong PGE 2 inhibitory activity in Example 4 TPA-induced mouse ear edema was used to assay the prednisolone, ugonin and flavanone, which are widely used as anti-inflammatory agents to compare with the anti-inflammatory action of the derivatives according to the present invention. Was used. That is, TPA (3 μg / ear) was applied once a day for 3 days, and the derivatives and positive controls according to the present invention were applied to the ears of the mouse 2 hours and 12 hours after TPA treatment, respectively, for 3 consecutive days. The elapsed time after TPA treatment was divided into 36 hours, 48 hours, and 52 hours to examine anti-inflammatory activity.
그 결과는 하기 표 4와 같고 따라서, 이들 유도체들은 양성 대조물질인 우고닌보다 강력한 항염증활성을 나타내었다.The results are shown in Table 4, and therefore, these derivatives showed stronger anti-inflammatory activity than the positive control, ugonin.
<표 4>TABLE 4
<실시예 9>Example 9
실시예 4에서 강한 PGE2 저해 활성을 나타낸 플라본 유도체 중에서 2',4',7-트리메톡시플라본 및 3',4'-디클로로-7-메톡시플라본을 대상으로 식품의약품안전청 고시에 따라 웅성의 ICR 마우스 및 SD 랫트를 대상으로 급성독성실험을 실시하였고, 상기 유도체들 모두 경구투여시 500 mg/kg까지의 용량에서 단회투여시 2주간 어떠한 독성도 나타나지 않았기 때문에, 이들 유도체들은 상용량에서 무독하다고 판단되었다.Among flavone derivatives showing strong PGE 2 inhibitory activity in Example 4, 2 ', 4', 7-trimethoxyflavones and 3 ', 4'-dichloro-7-methoxyflavones were tested according to the Korea Food and Drug Administration. Acute toxicity studies were conducted in ICR mice and SD rats, and all of these derivatives were not toxic at normal doses because they did not show any toxicity for two weeks at a dose of up to 500 mg / kg upon oral administration. Judging.
<제제예 1> 정제의 제조Preparation Example 1 Preparation of Tablet
본 발명에 따른 유도체를 50.0 mg, 옥수수전분 90.0 mg, 유당 175.0 mg, 엘-하이드록시프로필셀룰로오스 15.0 mg, 폴리비닐피롤리돈90 5.0 mg 및 에탄올 적량의 원료를 균질하게 혼합하여 습식과립법으로 과립화하고 스테아린산 마그네슘 1.8 mg을 가하여 혼합한 후 1정이 310mg이 되도록 타정하였다.50.0 mg of the derivative according to the present invention, corn starch 90.0 mg, lactose 175.0 mg, 15.0 mg L-hydroxypropyl cellulose, polyvinylpyrrolidone 90 5.0 mg and ethanol appropriately mixed raw material granules by wet granulation method 1.8 mg of magnesium stearate was added and mixed, and the tablets were tableted to 310 mg.
<제제예 2> 캅셀제의 제조Preparation Example 2 Preparation of Capsule
본 발명에 따른 유도체를 50.0 mg, 옥수수전분 83.2 mg, 유당 175.0 mg 및 스테아린산 마그네슘 1.8 mg의 원료를 균질하게 혼합하여 1캅셀에 310mg이 함유되도록 충전하였다.The derivative according to the present invention was homogeneously mixed with 50.0 mg, corn starch 83.2 mg, lactose 175.0 mg, and magnesium stearate 1.8 mg, and filled to contain 310 mg in one capsule.
이상에서 상술한 바와 같이, 본 발명은 화학식 1 내지 3으로 표시되는 신규한 플라본 유도체 및 약학적으로 허용가능한 이들의 염에 관한 것으로, 상기 플라본 유도체 및 약학적으로 허용가능한 이들의 염은 뛰어난 COX-2의 발현억제 및 활성억제 기능을 함과 동시에, 뛰어난 NO 생성억제 및 iNOS 활성억제 기능을 나타내므로, 화학식 1 내지 3으로 표시되는 신규한 플라본 유도체 및 약학적으로 허용가능한 이들의 염을 유효성분으로 함유하는 약학적 조성물은 염증질환, 면역조절 또는 암질환 예방에 효과적으로 사용될 수 있다.As described above, the present invention relates to novel flavone derivatives represented by Formulas 1 to 3 and pharmaceutically acceptable salts thereof, wherein the flavone derivatives and pharmaceutically acceptable salts thereof are excellent in COX- In addition to the function of inhibiting expression and activity of 2 and exhibiting excellent NO production and iNOS activity inhibitory functions, the novel flavone derivatives represented by Formulas 1 to 3 and pharmaceutically acceptable salts thereof as active ingredients Containing pharmaceutical compositions can be effectively used for the prevention of inflammatory diseases, immunomodulation or cancer diseases.
도 1은 본 발명에 따른 플라본 유도체의 PGE2 생성억제능을 나타내는 것이고, 1 shows PGE 2 production inhibitory ability of the flavone derivatives according to the present invention,
도 2는 본 발명에 따른 플라본 유도체의 COX-2 발현억제능을 나타내는 것이고, Figure 2 shows the COX-2 expression inhibitory ability of the flavone derivatives according to the present invention,
도 3은 본 발명에 따른 플라본 유도체의 iNOS 발현억제능을 나타내는 것이다. Figure 3 shows the iNOS expression inhibitory ability of the flavone derivatives according to the present invention.
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